The amyloid plaques made of Ab peptide and neurofibrillary tangles made of abnormal tau protein define the neuropathology of Alzheimer's disease. Many diverse studies support an initiating role for amyloid in Alzheimer's disease. However, these findings also clearly demonstrate both that the presence of tau is required for amyloid mediated neuronal dysfunction and that pathological tau protein causes neurodegeneration. Furthermore, pathological tau, including neurofibrillary tangles, characterizes the neuropathology of blast induced traumatic brain injury, chronic traumatic encephalopathy, and other related tauopathies. Traumatic brain injury is increasingly prevalent in the Veteran population. Both aging related changes and brain injury dramatically increase the risk for neurodegenerative dementia disorders. Thus it is imperative we develop treatments that can quickly bridge the gap between bench and bedside. Development of pharmacological interventions for tau mediated neurodegeneration is the long-term goal of this research project. Our drug discovery strategy employs an integrated approach aimed at expediting drug repurposing. Our previously published work demonstrated the effectiveness of these methods by screening a library of 1120 approved drugs to identify a single validated compound capable of ameliorating tau pathology in a transgenic mouse model of tauopathy. We now propose to extend this drug repositioning approach to a drug collection spanning most of the drugs with a history of clinical use (~5400 drugs). The objectives of this project are to: Identify compounds reducing tau aggregation in a transgenic C. elegans model of tauopathy and in a human cell culture model of tau aggregation; Prioritize hits based on their CNS penetration and identify dosing and routes of administration that modulate pathological tau in young mice; Use novel compounds identified above to intervene in symptomatic tauopathy mice. Completion of these studies will reveal FDA approved candidate drugs for use as tau targeted therapeutics for both Alzheimer's disease and blast induced traumatic brain injury, providing justification for the clinical testing of repurposed approved drugs for treatment of tauopathy disorders.